How genes influence the microbes in our mouths

No matter how much they brush their teeth, some people still get more cavities than others, in part because of differences in genetics and the make-up of the microbes in their mouths. A new study has found human genetic factors that influence the oral microbiome and may increase risk of cavities and tooth loss in some people. 
 
The study, led by scientists at the Broad Institute and Mass General Brigham, found a surprisingly large effect of human genetics on the abundance of microbes in the mouth. The researchers discovered genome-to-genome interactions between human DNA and the DNA of the oral microbiome. For example, they found that a human gene, AMY1, was strongly linked to the composition of the oral microbial community, and even to dentures use, suggesting that the relationship between this gene and the bacteria in the mouth plays a role in oral health. The paper, published today in Nature, is an analysis of the largest collection of oral microbiome profiles to date. 

“The abundance of many bacterial species in our mouths is strongly influenced by human genetics,” said study senior author Po-Ru Loh, associate member at the Broad and associate professor of medicine at Harvard Medical School and Brigham and Women's Hospital. “We know that the microbial environment in one person's mouth is going to be quite different from another person's mouth due to many factors, but genetics is a pretty strong one.”

Mouth to mouth

To find human-microbiota associations, the team analyzed whole-genome sequences from saliva-derived DNA from more than 12,500 individuals. Typically, the microbial DNA in human samples is tossed aside, but the team found a new purpose for the bacterial data sequenced together with each human genome. They measured the abundances of 439 common microbial species, and found 11 regions of the human genome associated with differences in the levels of dozens of species of bacteria in the mouth. 

“We also found that the same 11 human loci influence natural selection on dozens of different bacterial genes, so it seems like there's a lot of interaction between human genetics and the oral microbiome,” said study first author Nolan Kamitaki, a graduate student at Broad and Harvard Medical School.

Notably, the scientists found the strongest relationship between a genetic variant that breaks the FUT2 gene—which has previously been linked to gut microbiome composition—and the levels of 58 oral bacterial species.  
 
The researchers also leveraged data from the UK Biobank to analyze how human-bacteria interactions relate to oral health. One of the strongest associations they saw involved the AMY1 gene, which encodes a digestive enzyme found in saliva that breaks down starch into sugar. The team uncovered a link between the number of copies of this gene in a person’s genome and a change in the abundances of more than 40 oral bacterial species, many of which feed on sugars and over time build plaque.

Based on their biobank data analysis, they found that this same variation in the AMY1 gene correlated with an increase in dentures use, suggesting that having more copies of the gene can lead to higher rates of tooth decay by changing the ecology of the microbiota in the mouth. 

As part of this work, the team also devised clever strategies to run large-scale statistical testing in a more efficient way. With these new methods, they’re hoping other scientists will analyze even larger datasets in the future to uncover more associations between human genetics and the microbiome. 
 
“I hope these initial results can inspire the field to get excited about what you can learn about human genetic effects on microbiomes in general, but particularly oral microbiomes, because there seem to be such strong genetic effects,” Loh said.